Various amines have been reported as resolving agents for mandelic acid derivatives. For the resolution of mandelic acids a number of chiral amines have been described, e.g. α-methylbenzylamine, 2-benzylamino-1-butanol, (R)-2-tert-butyl-3-methylimidazolidin-4-one (BMI), (+)-cinchonine, brucine, quinine, quinidine, (−)-ephedrine, (−)-2-amino-1-butanol, amphetamine and adrenaline. These amines as well as others are described in E. J. Ebbers et al. Tetrahedron: Asymmetry 1997, 8, 4047-4057 and references cited therein.
In J. Hoover et al., (J. Med. Chem. 1974, 17, 34-41) are disclosed 21 substituted mandelic acids with references to original literature. The described resolving bases are (−)-ephedrine, brucine and (+)-α-methylbenzylamine.
J. Nieuwenhuijzen et al. (Angew. Chem. Int. Ed. 2002, 41, 4281-4286) describes the resolution of 4-chloromandelic acid with α-methylbenzylamine with or without a 1:1 ortho:para mixture of nitro-substituted α-methylbenzylamine (10 mol %).
JP2001072644 describes optical resolution of 2-chloromandelic acid with N-benzyl-α-methylbenzylamine and derivatives thereof. JP 1221345 describes optical resolution of phenyl-substituted mandelic acid derivatives with amino acid hydrazines.
However, there remains a need for further means for resolving mandelic acid derivatives. Mandelic acids are used in the manufacture of a range of interesting molecules, such as pharmaceuticals. Thus, the invention also relates to the use of the resolved mandelic acid derivatives as intermediates suitable for large-scale manufacturing of, for example pharmaceutical compounds, e.g. compounds as described in WO 02/44145.
A number of bases, including such described in the art, were tested in order to obtain acceptable resolution of mandelic acid derivatives (particularly 3-chloro-5-difluoromethoxymandelic acid), e.g. α-methylbenzylamine, (S)-1-naphthylethylamine, (+)-cinchonine, (+)-dihydroabietylamine, (S)-2-amino-2-phenylethanol, (−)-ephedrine, L-phenylalaniole, and α,α-diphenyl-D-prolinole. None of these yielded particularly satisfactory results for large-scale manufacturing purposes (having low yield and low enantiomeric excess). By large-scale we include manufacture of Kg quantities of material.
We have now surprisingly found that racemic mandelic acid derivatives may be resolved by salt formation with chiral base cyclic amides, such as proline amide.
We have also surprisingly found certain metal salts, and certain amine salts of mandelic acid derivatives (particularly (R)-3-chloro,5-difluoro-methoxy mandelic acid) which have desirable characteristics and are useful in manufacturing processes—see Example 12 and claims hereinafter.